tbuckley/cabot-search huggingface dataset:
Abstract LB155: In vivo imaging of vascular pathology in mouse orthotopic glioma model using functional ultrasound
Authors: Jussi Rytkönen, Kimmo Lehtimäki, Taina-Kaisa Stenius, Riikka Immonen, Ari Suhonen, Artem Shatillo
Journal: Cancer Research (2023)

Abstract Neovascularization together with aberrant vasculature is a hallmark of glioblastomas. Understanding tumor vasculature can have a pivotal role in planning therapeutics approaches. The objective of this study was to investigate morphological, vasculature and blood flow changes induced by aggressive tumor growth, using in vivo imaging - magnetic resonance imaging (MRI) and functional ultrasound (fUS) imaging in a mouse model of orthotopic glioma. Female NMRI nude mice were xenografted orthotopically with U-87 MG, a human glioblastoma, cells (5 × 104) at the age of 8 weeks. Four weeks after implantation the mice we anesthetized with isoflurane and scanned with 11.7 T small animal MRI (Bruker) for tumor volumetry. Thereafter, the mice were imaged with Iconeus One imaging system (Iconeus, Paris, France) for structural information of brain vasculature and relative cerebral blood volume (rCBV) changes. High resolution vascular imaging was performed after intravenous injection of microbubble contrast agent (SonoVue, sulphur hexafluoride microbubbles). The average tumor size was 58.8 ± 27.6 mm3 (mean ± SD, n=7) four weeks after implantation. Aberrant vasculature could be visualized with structural fUS imaging as and the necrotic core of the tumor could be observed. A reduced rCBF was observed in ipsilateral hemisphere on the relative power doppler signal timeseries as a lower amplitude and faster decay compared to contralateral side. As a summary, in vivo fUS imaging is a noninvasive tool to visualize vascular changes induced by aggressive brain tumor growth which are not detectable with conventional imaging methods (CT, MRI, PET, SPECT) and can provide a novel readout for efficacy studies. Citation Format: Jussi Rytkönen, Kimmo Lehtimäki, Taina-Kaisa Stenius, Riikka Immonen, Ari Suhonen, Artem Shatillo. In vivo imaging of vascular pathology in mouse orthotopic glioma model using functional ultrasound [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB155.
Abstract LB183: Network biology approach reveals multiple non-essential helper genes to target cancer cell lethality
Authors: Yongsheng Li, Nidhi Sahni, S. Stephen Yi
Journal: Cancer Research (2023)

Abstract Understanding the determinants of human gene essentiality is critical for developing anticancer therapeutics. Here, we systematically analyzed the human essentialome from a network perspective. We found that essential genes are mostly context-specific and predicted synthetic lethal interactions based on analysis of context-specific essentiality in distinct genetic backgrounds. The predicted gene pairs are significantly overlapped with known synthetic lethality and further validated across more than 300 cancer cell lines. Moreover, analysis of synthetic lethal interactions among actionable genes helps prioritizing rational drug combinations. Surprisingly, genes in human essentialome (especially spliceosome, RNA transport and cell cycle genes) are enriched for cancer mutations with high functional impact and disease risks. Our network analyses suggest that protein interactome topology and neighborhood community integrated with gene expression, are highly predictive of gene essentiality. Thus, we devised network-based method (SYE-NET) to systematically prioritize the essentialome, which is further validated by functional screens in independent cell lines. Taken together, our study provides a holistic insight into molecular determinants for cell fate and implicates potential biomarkers for synthetic lethality and drug combinations in cancer, a critical step towards precision medicine. Citation Format: Yongsheng Li, Nidhi Sahni, S. Stephen Yi. Network biology approach reveals multiple non-essential helper genes to target cancer cell lethality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB183.
Abstract LB347: A lung-mimicking synthetic metastatic niche reveals N1 neutrophils drive breast cancer metastatic dormancy in the lungs
Authors: Jing Wang, Ramon Ocadiz-Ruiz, Matthew Hall, Grace Bushnell, Sophia Orbach, Joseph Decker, Ravi Raghani, Yining Zhang, Aaron Morris, Jacqueline Jeruss, Lonnie Shea
Journal: Cancer Research (2023)

Abstract 3D scaffolds mimicking the environment in the primary tumor or metastatic organs can deconstruct complex niche signals and facilitate the study of cancer progression and metastasis. Here, we reported that a subcutaneous 3D scaffold implant acted as a lung-mimicking dormant metastatic niche in mouse models of metastatic breast cancer, recruiting lung-tropic circulating tumor cells yet suppressing their growth through potent in situ antitumor immunity. We compared it with the immunosuppressive lungs developing lethal metastases and the dormant lungs suppressing tumor growth derived from breast cancer models with varying tumor aggressiveness and host immunity. Our data suggested that breast cancer-induced Gr1+CD11b+Ly6G+ granulocytic myeloid cells (neutrophils) infiltrated the scaffold implants and lungs, secreting the same signal to facilitate the metastatic seeding of lung-tropic cancer cells in these two types of niches. However, circulating neutrophils with opposing phenotypes and functions (N1 and N2) were selectively recruited and enriched in the dormant scaffolds/lungs and immunosuppressive lungs, respectively, responding to two distinct groups of chemoattractants. N1 or N2 neutrophils established activated or suppressive immune environments in the metastatic niches, directing different fates of cancer cells. The clinical relevance of these scientific findings was validated by the strong positive correlation of a high N1-to-N2 neutrophil chemoattractant ratio with a low-grade primary tumor, a low metastases incidence, and a better prognosis in breast cancer patients. Overall, our study revealed the multifaceted roles of neutrophils in regulating lung metastasis and underscored the importance of N1 neutrophils in driving breast cancer metastatic dormancy in the lungs, inspiring next-generation immunotherapy. Citation Format: Jing Wang, Ramon Ocadiz-Ruiz, Matthew Hall, Grace Bushnell, Sophia Orbach, Joseph Decker, Ravi Raghani, Yining Zhang, Aaron Morris, Jacqueline Jeruss, Lonnie Shea. A lung-mimicking synthetic metastatic niche reveals N1 neutrophils drive breast cancer metastatic dormancy in the lungs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB347.
Abstract CT189: A phase I study of BAT1006, a novel anti-HER2 antibody, in patients with locally advanced/metastatic solid tumors
Authors: Xingxing Mei, Weijia Tang, Shuqiang Song, Hao Wang, Chuanqi Cao, Cuiying Feng, Bert E. Thomas, Shengfeng Li, Jin-Chen Yu
Journal: Cancer Research (2023)

Abstract Purpose: BAT1006 is a HER2 extracellular domain II-targeted monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effect aiming for Her2-positive locally advanced/metastatic solid tumors. Previous studies have shown that de-fucosylated antibody binds to FcγRIIIa with increased affinity and can thus trigger FcγRIIIa-mediated effector functions more efficiently than native antibody. BAT1006 was expressed in an FUT8-knockout CHO cell line, resulting in antibody completely devoid of fucose modification. With approximate 5-fold higher level of ADCC effect compared to Pertuzumab, BAT1006 also exhibited potent anti-tumor activity in HER2 positive Calu-3 xenograft mice model. The ongoing phase I, open-label, first-in-human study is evaluating the safety, pharmacokinetics (PK), immunogenicity and preliminary efficacy of BAT1006 to determine the Maximum-Tolerated Dose (MTD) and/or recommended phase II dose (RP2D). Methods: Patients with locally advanced/metastatic solid tumors received escalating doses of BAT1006 (3, 6, 10, 15 mg/kg), administered intravenously (IV) once every three weeks. Patients must have had documented HER2 positivity defined as 3+ by validated immunohistochemistry or amplified on in situ hybridization (ISH). Assessments include archival tumor molecular status, PK, and efficacy by Response Evaluation Criteria in Solid Tumors (RECIST). Results: Fifteen patients [with 2-9 prior lines of therapy] have been treated with BAT1006. All patients had metastatic breast cancer and had received previous HER2-targeted therapies including Trastuzumab, Pertuzumab, T-DM1 and Pyrotinib. No treatment related ≥ Grade 3 AEs have been observed. Of 9 patients at 10mg/kg and 15mg/kg, 1 in 3 patients had CR at 10mg/kg, 2 in 6 patients had PR at 15mg/kg. Conclusion: BAT1006 was well tolerated and showed promising anti-tumor activity in patients with heavily pre-treated HER2-positive cancers. Based on the safety and efficacy results, one additional dose level (20 mg/kg) will be added to the escalation phase and combination therapy with other HER2-based therapy will also be initiated. Citation Format: Xingxing Mei, Weijia Tang, Shuqiang Song, Hao Wang, Chuanqi Cao, Cuiying Feng, Bert E. Thomas, Shengfeng Li, Jin-Chen Yu. A phase I study of BAT1006, a novel anti-HER2 antibody, in patients with locally advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT189.
Abstract LB081: Concurrent characterization of somatic nucleotide mutations, 5mC, and 5hmC methylation in clinical research samples using a single nanopore sequencing assay
Authors: Sergey Aganezov, Philipp Rescheneder, John Beaulaurier, Phillip James, Sissel Juul
Journal: Cancer Research (2023)

Abstract Genomic and epigenomic variants accumulate during cancer progression, resulting in a tumor consisting of heterogeneous collections of cells, or clones, with distinct profiles of genomic and/or epigenomic alterations. The ability to characterize a broad set of somatic (epi)genomic variations simultaneously, using a single sequencing assay, facilitates cancer research and can help inform treatment. Here we describe a comprehensive approach to analyze native tumor DNA with long nanopore reads. First, we demonstrate that shallow (&amp;lt;1x) whole genome nanopore sequencing provides sufficient information to observe large-scale copy number aberrations. This enables rapid and affordable screening of samples with an aim of selecting those that contain variation(s) of potential interest; such samples can then be sequenced to higher coverages for a higher resolution picture of specific structural variants. We further demonstrate an analysis workflow vimba for high coverage (&amp;gt;30x) nanopore sequencing of tumor/normal datasets that detects clone- and haplotype-resolved structural variations in patient-derived research samples. We provide an example of haplotype- and breakpoint-resolved compounded amplification and loss of heterozygosity (LOH) of a region containing the EGFR gene in an admixed kidney tumor sample. Finally, we describe the suitability of this assay to gather genome-wide (epi)genomic variations (e.g., SNPs, indels, SVs, microsatellite instability) across tumor samples of different cancer types. For the first time with native long nanopore reads we are able to capture 5mC and 5hmC methylation information and map it over some of the most challenging repetitive regions of the genome. This information can empower a better understanding of cancer-type-specific (epi)genomic alterations, which in turn can help map out the landscape for further research. Our approach demonstrates how nanopore sequencing can be used as a single comprehensive platform to better understand and resolve the complexity of (epi)genomic somatic alterations in tumor samples. Citation Format: Sergey Aganezov, Philipp Rescheneder, John Beaulaurier, Phillip James, Sissel Juul. Concurrent characterization of somatic nucleotide mutations, 5mC, and 5hmC methylation in clinical research samples using a single nanopore sequencing assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB081.
Abstract LB274: Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance
Authors: Xuefeng Dou, Judith Campisi, Yu Sun
Journal: Cancer Research (2023)

Abstract Cellular senescence is a permanent state of cell cycle arrest and occurs in proliferating cells subjected to various stresses. Although senescent cells remain metabolically active, little is known about their metabolic landscape and in vivo pathophysiological implications. Here we show that expression of the pyruvate dehydrogenase (PDH) inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells. Preferentially expressed upon genotoxicity-induced senescence, PDK4 is negatively correlated with posttreatment survival of cancer patients. Upon cellular senescence, PDK4 shifts glucose metabolic flux from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, causing enhanced lactate production and forming an acidic microenvironment. However, distinct from the cancer cell-featured ‘Warburg effect’, senescent cells maintain an intensive use of pyruvate through the tricarboxylic acid cycle (TCA), displaying increased respiration and redox activity, indicative of a special form of metabolic reprogramming. Conditioned media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro and accelerate tumor progression in vivo. Nevertheless, specific targeting PDK4 curtails the adverse effects of senescent cells in cell-based assays, while promoting tumor regression and extending posttreatment survival in preclinical trials. Of note, increased levels of lactate in circulating blood after chemotherapy predicts lower survival in cancer clinics. PDK4 upregulation and ensuing lactate production are thus among key features of senescence, in addition to the established cell-autonomous and non-cell-autonomous hallmarks of senescent cells, providing a novel therapeutic target for future clinical oncology. Together, our study substantiates the hypercatabolic capacity of senescent cells, and reveals a metabolic link between senescence-associated acidic microenvironment and age-related pathologies, including but not limited to cancer. Citation Format: Xuefeng Dou, Judith Campisi, Yu Sun. Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB274.
Abstract LB115: Simultaneous whole-body ultrasound contrast imaging: a novel high throughput preclinical platform for targeted molecular imaging studies
Authors: Arutselvan Natarajan, Farbod Tabesh, Dongwoon Hyun, Ramasamy Paulmurugan, Jeremy Dahl
Journal: Cancer Research (2023)

Abstract Ultrasound contrast agent (UCA) based molecular imaging is a rapidly growing field in biomedical research. Ultrasound (US) is a non-radiative imaging modality that is frequently used to investigate various human diseases in the clinic. US molecular imaging is a novel imaging modality that utilizes targeted contrast agents to add molecular information about the imaging target, including vascular biomarkers of cancer. Pre-clinical animal models are commonly used to evaluate and validate targeted contrast agents before extending them for FDA-approval. Key impediments in the preclinical evaluations are the short in vivo half-life of microbubbles (MBs) (less than 30 minutes), limited transducer scanning area, and focusing one target at a time, which all make this strategy low throughput. Moreover, whole-body imaging strategy is not available for US imaging compared to other imaging modalities, such as PET, CT, and MRI. To overcome these imitations, we have developed a multi-mouse US imaging platform using an Automated Breast Volume Scanner (ABVS) system. In addition, we have synthesized a novel breast cancer vascular-specific B7-H3 targeted microbubbles (TMBs) using a microfluidic device. We tested these TMBs in a genetically engineered transgenic mice model [FVB/N-Tg (MMTV-PyMT)634Mul/J] (n=32) that develops breast cancer in the mammary fat pad. The US imaging results of conventional Vevo 2100 system indicated that B7-H3-TMBs could provide target specific contrast signals in the tumor vasculature compared to control MBs. We used this MBs for whole-body imaging using an ABVS system with two mice simultaneously in a stage. We imaged multiple tumors (10 tumors/mouse, 2 mice per scan, n=20 tumors) with a single bolus injection of TMBs per mouse. The results successfully showed tumor specific contrast signals from tumors independent of tumor size. Introduction of this whole-body scanner, and its ability to scan multiple mice simultaneously allows rapid imaging of multiple tumors with 3D quantification of tumor size by administering a single TMB injection enabling without significant contrast loss. Our approach makes this US-MI as high throughput and can be used to test multiple contrast agents for investigating different aspects of biological problems including screening of vascular biomarkers of human diseases. Citation Format: Arutselvan Natarajan, Farbod Tabesh, Dongwoon Hyun, Ramasamy Paulmurugan, Jeremy Dahl. Simultaneous whole-body ultrasound contrast imaging: a novel high throughput preclinical platform for targeted molecular imaging studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB115.
Abstract LB040: P62-mediated degradation of TIF-IA drives the senescence associated secretory phenotype
Authors: Hazel Thoms, Lesley Stark
Journal: Cancer Research (2023)

Abstract Advanced age is one of the most significant risk factors for malignancy. One mechanism proposed for age-associated cancer risk is the accumulation of senescent cells in ageing tissue. These cells secrete a cocktail of pro-tumorigenic factors known as the senescence associated secretory phenotype (SASP). The SASP is driven by the NF-κB transcription factor. However, the initial triggers of NF-κB in senescence remain unclear. Here we describe a novel mechanism that triggers NF-κB and the SASP. Using multiple in vitro and in vivo models, we demonstrate accumulation and cytoplasmic to nuclear translocation of the PolI complex component, TIF-IA, upon senescence induction. siRNA knockdown revealed TIF-IA is not required for the cell cycle effects of senescence but is essential for transcription of SASP factors, nucleolar enlargement (a characteristic of senescence and marker of organismal ageing) and full senescence. We make the novel observation that in steady state, TIF-IA is targeted for autophagosomal degradation by the cargo receptor, p62, which is inhibited in senescence and promoted by inactivation of the DNA repair protein, ATM. Based on these data, we propose a model whereby the P62-TIF-IA interaction is lost downstream of DNA damage and ATM activation, which causes TIF-IA accumulation, the SASP and senescence. Using tissue from the well characterized nfkb1− / − mouse model of aging, and old and young mice, we show that TIF-IA accumulates in colonic mucosa with age, which is further enhance by nfkb1 deletion. These exciting new data identify a new role for TIF-IA and have considerable relevance to age-related cancer. Citation Format: Hazel Thoms, Lesley Stark. P62-mediated degradation of TIF-IA drives the senescence associated secretory phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB040.
Abstract LB339: PARP inhibition reprograms CD8 T cells, enhancing their function and generation of prolonged memory, leading to greater anti-tumor immune response
Authors: Wael Traboulsi, Subhadip Kundu, Pankaj Gaur, Zainab Ramlaoui, Dareen Sarhan, Nour Shobaki, Jacob Lee, Nazli Jafarzadeh, Simon T. Barry, Viia E. Valge-Archer, Vivek Verma, Seema Gupta, Samir N. Khleif
Journal: Cancer Research (2023)

Abstract Olaparib is the most widely studied third-generation PARP inhibitor (PARPi) in clinical practice with a significant clinical outcome in BRCA deficient tumors such as breast and ovarian cancers. However, innate and adaptive resistance in patients with DNA damage repair (DDR) gene mutations were reported after treatment with PARPi, highlighting the potential implication of other compartments such as the role of immune cells in the mechanism of resistance. Importantly, PARPi is shown to have an immune-modulatory capacity within the tumor microenvironment (TME) by activating the STING pathway and increasing interferon gamma (INF-gamma) and chemokine secretion and hence increasing the recruitment and function of CD8 T cells. In addition, PARPi is shown to affect other cells within the TME such as, macrophages, myeloid-derived suppressor cells (MDSCs) and cancer associated fibroblasts (CAFs), promoting either an immune enhancement or immune suppressor milieu that could indirectly affect CD8 T cell function. However, little is known about the direct effect of PARPi on CD8 T cells. In this study using two cold tumor models, we show that PARPi controls the tumor growth and increases survival in tumor-bearing mice. This effect is due to the enhancement of number and cytotoxicity of antigen-specific CD8 T cells and the maintenance of memory population within the TME. In vitro study shows that PARPi activates the SIRT-1/FOXO1 pathway, leading to the modification of gene expression related to memory and fatty acid oxidation (FAO) metabolism in CD8 T cells. As a result, a unique subpopulation of superior central memory cells with high recall responses and anti-tumor effects are generated after PARPi treatment. Interestingly this unique subpopulation was also generated after PARPi in human cells. Together, our findings highlight the direct effect of PARP inhibition on CD8 T cells and its ability to modulate and reprogram CD8 T cells within the TME, leading to a greater anti-tumor immune response. Citation Format: Wael Traboulsi, Subhadip Kundu, Pankaj Gaur, Zainab Ramlaoui, Dareen Sarhan, Nour Shobaki, Jacob Lee, Nazli Jafarzadeh, Simon T. Barry, Viia E. Valge-Archer, Vivek Verma, Seema Gupta, Samir N. Khleif. PARP inhibition reprograms CD8 T cells, enhancing their function and generation of prolonged memory, leading to greater anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB339.